Not Applicable
The present invention relates to a device for the combined use of electrotransport or phonophoresis with a chemical permeation enhancer in order to facilitate transnasal or transocular drug delivery to the nervous system of a mammal.
A variety of routes currently exist for delivering drugs with a therapeutic and/or diagnostic effect on a mammalian organism, herein termed xe2x80x9cdrugsxe2x80x9d, to the nervous system of a mammal. Examples of such routes include, among possible others, oral administration, transcutaneous or transmucosal absorption, as Ill as intravenous, subcutaneous or intramuscular injections. All of these routes of drug delivery are based on the administration of a drug into the general bloodstream, wherein the drug is delivered by the bloodstream systemically to all organs and tissues. Because all of the body organs are exposed to relatively high concentrations of a drug during systemic delivery, there is a potential for adverse effects and iatrogenic complications that may be quite severe with
It is very important to consider the anatomy of the olfactory region of a mammal including human. The olfactory area is quite different between primates and lower animals. The anatomy of the nasal passages is quite complex (human nasal cavity is illustrated in FIG. 1; Anthony Wexler, personal communications). The olfactory fissure leading to the cribriform plate at the roof of the nose is very narrow; ranging from complete closureto 3-4 mm when a decongesting agent is used (Guilmette, R. A., Wicks, J. D. and Wolff, R. K., Morphometry of Human Nasal Airways In Vivo Using Magnetic Resonance Imaging, J. Aerosol Med., Vol. 2, No. 4, pp. 365-377, 1989). It is obvious that a drug-containing device in a liquid or semi-liquid form will be preferred to enter such a difficult to access region and to make an intimate contact with the olfactory mucosa in every part of the olfactory region including the olfactory fissure and the cribriform plate. certain drugs. This problem of systemic side effects can be particularly aggravated when drugs must be given relatively frequently and/or few therapeutic alternatives exist.
When a drug has to be delivered to the central nervous system (CNS), it is first administered into the systemic bloodstream. Once the drug has been distributed throughout the bloodstream, it has to penetrate a complex system of tight endothelial junctions in the capillaries supplying the CNS comprising the so-called blood-brain barrier (BBB). The blood capillaries of the BBB are relatively impermeable to large molecules, particularly the charged, polar or ionizable ones. Thus, the BBB serves the function of keeping the environment of central nervous system constant and preventing potentially harmful molecules from passing from the bloodstream through the BBB into the CNS. Holver, many useful drugs are unable to efficiently penetrate the blood-brain barrier and reach therapeutic concentrations in the CNS. Yet others create therapeutic levels in the CNS only when their concentration in the bloodstream is increased to dangerously high levels, which leads to increased incidence of severe adverse effects, such as liver damage or kidney failure. There are also drugs that penetrate the BBB relatively Ill but cause severe systemic side effects on other organs when administered in the general bloodstream even at low concentrations.
Many drugs have a net charge, or have a polar structure, or are ionizable, or have a large molecular size. As a result, any of these drugs are unable to efficiently penetrate biological membranes (largely composed of hydrophobic lipids) including those comprising the superficial protective layer termed epidermis, or mucous membranes such as nasal mucosa. Holver, even uncharged and non-polar drugs may be significantly impeded in their transport across the BBB if, for example, the drug tends to form a large molecular complex with itself or with other molecules in the bloodstream such as albumin protein. In order to facilitate the delivery of drugs with poor penetration potential, several approaches of physical or chemical enhancement have been proposed.
For the purpose of this invention, xe2x80x9celectrotransportxe2x80x9d is defined as any form of electrically assisted delivery of a substance through a mammalian tissue, such as nasal mucosa, at least partially induced or enhanced by the application of an electrical potential. Thus, the term xe2x80x9celectrotransportxe2x80x9d as used herein includes without limitation previously defined terms such as iontophoresis, electrotransport, iontokinesis, electroporation and electroosmosis, and the combination of, which comprises the transport of a substance (either charged or neutral) at least partially induced or enhanced by the application of an electric potential, as in U.S. Pat. Nos. 5,298,017, 5,736,580, 5,749,847. In any given electrotransport process, hoIver, more than one of these processes may be occurring simultaneously to a certain extent. In the present disclosure, the term xe2x80x9celectrotransportxe2x80x9d is used in its broadest possible interpretation so that it includes the electrically induced or enhanced transport of a biomolecular agent, which may be charged or uncharged, or a mixture thereof, regardless of the specific mechanism(s) of transport. A drug can therefore travel into and across the nasal mucosa, and/or across cell membranes into the olfactory nerve terminals, and/or through the cribriform lamina (located at the roof of the nose in the olfactory region) and across soft tissues along the olfactory pathway, and/or into the cerebrospinal fluid (CSF). For example, the term electrotransport as used herein includes without limitation electroporation folloId by iontophoresis and/or electroosmosis, or iontophoreses and/or electroosmosis folloId by electroporation.
The term xe2x80x9cphonophoresisxe2x80x9d as used here is defined without limitation as any form of transport of a substance through mammalian tissue induced or enhanced by the application of ultrasound. The biomolecular agent can thereby travel into or across the treated tissue, and/or across the cell membrane into the cell, and/or across the nuclear membrane into the nucleus. For examples of ultrasound enhancement of drug delivery see U.S. Pat. Nos. 4,948,587 and 4,767,402 the disclosures of which are incorporated herein by reference in their entirety.
As described in U.S. Pat. No. 5,023,085 the disclosures of which are incorporated herein by reference in their entirety, iontophoresis can be combined with the use of a chemical or biological agent enhancing transdermal flux to achieve an increased efficiency of drug delivery across the skin for both topical and systemic drug delivery. As described in U.S. Pat. No. 5,624,898 the disclosures of which are incorporated herein by reference in their entirety, some lipophilic substances can augment the passive absorption of a limited group of neurologic agents from nasal cavity into olfactory nerve terminals with subsequent neuronal transport to the brain. In addition, PCT Patent Application PCT/EP96/05086 of Nov. 21, 1996 (WO 97/18855, published May, 29 1997) the disclosures of which are incorporated herein by reference in their entirety, discloses a drug delivery system that employs iothophoresis or phonophoresis in order to enhance drug transport, whereas a drug can be delivered from the nasal cavity directly into the CNS, without entering the general blood circulation, through the olfactory pathway, or through the sclera or cornea of the eyeball and via the ocular neural pathway. This approach is neither topical nor systemic, but rather involves delivery of a drug from the nasal cavity or an ocular surface area to a remote site in the CNS. Thus, the disclosed system provides a high efficiency enhancement of drug delivery to the CNS and allows controlling the rate of drug administration. HoIver, in some circumstances, this approach results in a new problem of causing local damage to the tissues directly underlying the active electrode created by a large amount of current and/or the extended duration of electrotransport necessary to deliver a therapeutic amount of a drug to the CNS.
This problem is further aggravated by the fact that the nasal mucosa in general and the olfactory neuroepithelium in particular are much more delicate and susceptible to damage than skin. Furthermore, the olfactory neuroepithelium is a very specialized type of epithelium that has a limited surface area and a poor regeneration potential. For these reasons, it is very important to use the loIst possible electrical potential and current density, and to deliver the least amount of current, as Ill as to limit the duration of electrotransport. HoIver, when this is done in an attempt to limit tissue damage and patient discomfort, the efficiency of drug delivery is greatly decreased and the therapeutic value of the treatment is similarly reduced.
Thus, none of the methods disclosed in the patents referenced above results in a combination of high efficiency and low side effects delivery of drugs to the CNS. Therefore, there still exists a need to further optimize enhanced delivery of drugs to the CNS. As a result, the present invention focuses on the use of electrotransport or phonophoresis (as defined above) in combination with at least one or more chemical permeation enhancer, which greatly increases the efficiency of drug delivery, and/or decrease the potential side effects. A chemical permeation enhancer may be chosen from a large group of substances know to those skilled in the art, including but not limited to transmucosal or transdermal flux enhancers, substances that promote the absorption of a drug through the olfactory epithelium and into the olfactory neural system, substances that promote transscleral or transcorneal drug penetration, substances that facilitate the transport of a drug along the olfactory or visual pathway, substances that specifically target the CNS, or any particular region within the CNS, or peripheral olfactory or visual neural systems, as Ill as any possible combination of the above substances.
Already in 1740 Pivati introduced iontophoresis to treat arthritis and the general systemic effects of the physical enhancement technique was first observed by Munch in 1879 when strychnine killed his test animal. In the beginning of the 20th Century Leduc performed his famous experiments that demonstrated the potential of iontophoresis as drug delivery technique.
At present, iontophoresis as a non invasive drug delivery technique is being used in many areas of medicine like anesthesiology, pediatrics, general and orthopedic surgery, dentistry, dermatology, physical therapy, otolaryngology, and ophthalmology. Dermatologists use iontophoresis in the treatment of hyperhidrosis, plantar warts, lichen planus, scleroderma, infected burn wounds and for inducing local skin anesthesia. Physical therapists used corticosteroid iontophoresis to treat bursitis and other musculoskeletal disorders. Lidocaine iontophoresis has been successfully used by ear nose throat specialists as a local anesthetic treatment of the ear. Dentists use iontophoresis to deliver sodium fluoride, methylprednisolone in the treatment of hypersensitive teeth. More recently ophthalmologists have successfully achieved local anesthesia for short-term eyelid surgery. Also antibiotics have been delivered into the eyes by means of iontophoresis.
Due to the many iontophoresis applications, there were many (several hundreds) types of iontophoresis electrodes described and disclosed throughout the 20th Century. Each electrode is adapted to its specific use. It is evident that an electrode used in dentistry, will not be appropriate to deliver antibiotics through the cornea of the eye, though the mechanism principle of iontophoresis is in all these electrodes the same: transport of ionized compounds as a result of an externally applied electric field.
The presently disclosed method is based on nasal iontophoresis, in order to discriminate intranasal iontophoresis, for local treatment or for systemic delivery of medicaments through the respiratory nasal epithelium directly into the systemic circulation from nasal delivery via the olfactory mucosa directly into the CNS, Applicant preferred to use the term transnasal iontophoresis to indicate the long distance transfer of drugs from the nose to the brain.
In contrast to drug delivery through the respiratory epithelium of the nasal cavity, Applicant""s method is based on drug delivery through the olfactory epithelium of the nasal cavity. Systemic nasal drug delivery implicates that drugs are delivered through the respiratory epithelium of the nasal cavity. This epithelium is easy accessible by means of nose drops and nasal sprays. However the major reason why respiratory epithelium is the target site of nasal drug administration is its rich underlying vascular network, especially in the Kiesselbach""s area. These blood vessels can be accessed immediately following absorption and blood flow distributes the drug throughout the rest of the body. Vascularization in the olfactory region is much less compared to the anterior part of the nasal cavity.
The respiratory epithelium or respiratory mucosa covers the wall of the large central portion of the nasal passages. It is a highly vascular pseudostratified columnar tissue, which is constituted of three principal cell types including columnar cells, goblet cells and basal cells (Geurkink 1983, J. Allergy Clin.Immunol.,, 72,123-128). Ciliated columnar cells are the predominant cells, although non-ciliated columnar cells also exist in this region. The cilia beat in wave- like motion that moves the mucous and any particles therein to the posterior nasal cavity. The cilia are surrounded by tiny microvilli, which also aid in maintaining the flow of the mucous layer. Mucous secreting goblet cells are also columnar in shape and have microvilli on their surface. Basal cells sit on the basal membrane along with many columnar and goblet cells, but they do not extend up to the mucosal surface of the epithelium.
The mucous layer of the respiratory epithelium is lined with a layer of clear mucous that is in constant motion due to the powerful movements of the cilia present in the respiratory region. The mucous layer is removed and replaced about every ten minutes.
The olfactory epithelium or olfactory mucosa is a pseudostratified columnar neuroepithelium, which is comprised of three principal cell types including receptor or olfactory cells, supporting cells and basal cells. The cell type that differentiates olfactory epithelia from other types of epithelia is the receptor cell or also known as the primary olfactory neuron (cranial nerve I). They are elongated columnar like bipolar cells, which have cell bodies located at various depths within the neuroepithelium. Within the neuroepithelium, the receptor cell vesicles are rod-shaped, but at the mucous surface the diameter expands becoming knob-like, and many long immotile dendritic cilia filled with protoplasm extend into and are surrounded by the mucous. The supporting cells are covered with microvilli and extend from the mucous surface of the neuroepithelium to the basal membrane. The basal cells of the olfactory mucosa are similar in position to those in the respiratory epithelium. Unlike the basal cells in the respiratory epithelium, these cells further differentiate to become receptor cells (Graziadei P. P. C. and Monti-Graziadei, 1985, Ann.NY.acad.Sci.,457,127-145)
Unlike the respiratory epithelium, the mucous layer in the olfactory epithelium does not have motile cilia to facilitate flow. Instead, the mucous layer is viscous and stationary, being removed from the surface only by over production by the mucous glands in the epithelium.
Therefore, it is an object of the present invention to provide an efficient and safe means for drug delivery to the nervous system that allows an optimal therapeutic concentration of a drug to be created in the nervous system of a mammal. Another object of the invention is to provide a reliable method of drug delivery that combines the use of both physical and chemical enhancement methods in order to facilitate drug transport to the nervous system from a remote site corresponding to a distal ending of a neural pathway. Yet another object of the invention is to combine the use of electrotransport or phonophoresis with a variety of chemical permeation enhancers in order to provide the desired physical and chemical enhancement of drug delivery. Still another object of the invention is to use these methods for the enhanced delivery of drugs to the nervous system of a mammal through the transnasal or transocular pathways.
The efficient and safe delivery of therapeutic amounts of a drug into the nervous system can be achieved by combining the use of a physical enhancement means with at least one or more chemical permeation enhancers. Specifically, the use of a combination of either electrotransport or phonophoresis or both with a chemical permeation enhancer increases the amount of a drug delivered to the nervous system of an individual with feIr and less prominent side effects. The drug delivered by the method of the disclosed invention can be any suitable substance that has an effect on the organism of the recipient, including, but not limited to, traditional pharmaceuticals and therapeutics, nutritional supplements and vitamins, as Ill as nucleic acids, peptides and other macromolecules. Using the methodology of the disclosed invention, drugs are delivered to the CNS via transnasal or transocular rout.
Therefore, the combined use of electrotransport or phonophoresis with a chemical permeation enhancer results in a significant enhancement of the ability to deliver a drug to the CNS. As a result, lesser amounts of the drug can be used initially, which results in a reduction in cost which may be significant particularly in case of expensive drugs such as nucleic acids and peptides. In addition, the duration of the delivery procedure can be shortened, and lesser amount of electrical charge or ultrasound applied is needed to effectuate the use of electrotransport or phonophoresis respectively in order to deliver the desired amount of drug, thus resulting in feIr and less pronounced side effects. These modifications will result in the improvement of patient""s comfort which will increase his compliance with treatment. The use of electrotransport or phonophoresis provides an efficient mechanism for controlling the rate of drug delivery, which is difficult to achieve with a chemical permeation enhancer alone. In this way, the disadvantages of the prior art can be overcome.
Other objects, features and advantages will be apparent from the following detailed description of preferred embodiments thereof taken in conjunction with the accompanying drawings in which: